Objective: Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30-50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes. Increased knowledge of OCCC-specific genetic aberrations may help in guiding development of targeted treatments and ultimately improve patient outcome. Methods: Gene expression profiling of formalin-fixed, paraffin-embedded (FFPE) tissue from a cohort of the major ovarian cancer subtypes (cohort 1; n = 67) was performed using whole-genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL) bead arrays, followed by pathway, gene module score, and gene ontology analyses, respectively. A second FFPE cohort of 10 primary OCCCs was analyzed by targeted DNA sequencing of a panel of 60 cancer-related genes (cohort 2). Non-synonymous and non-sense variants affecting single-nucleotide variations and insertions or deletions were further analyzed. A tissue microarray of 43 OCCCs (cohort 3) was used for validation by immunohistochemistry and chromogenic in situ hybridization. Results: Gene expression analyses revealed a distinct OCCC profile compared to other histological subtypes, with, e.g., ERBB2, TFAP2A, and genes related to cytoskeletal actin regulation being overexpressed in OCCC. ERBB2 was, however, not overexpressed on the protein level and ERBB2 amplification was rare in the validation cohort. Targeted deep sequencing revealed non-synonymous variants or insertions/deletions in 11/60 cancer-related genes. Genes involved in chromatin remodeling, including ARID1A, SPOP, and KMT2D were frequently mutated across OCCC tumors. Conclusion: OCCCs appear genetically heterogeneous, but harbor frequent alterations in chromatin remodeling genes. Overexpression of TFAP2A and ERBB2 was observed on the mRNA level in relation to other ovarian cancer subtypes. However, overexpression of ERBB2 was not reflected by HER2 amplification or protein overexpression in the OCCC validation cohort. In addition, Rho GTPase-dependent actin organization may also play a role in OCCC pathogenesis and warrants further investigation. The distinct biological features of OCCC discovered here may provide a basis for novel targeted treatment strategies.

Communicating cancer risk and recommending adequate control programs is central for genetic counseling. Individuals affected by hereditary nonpolyposis colorectal cancer (HNPCC) are at about 80% life-time risk of colorectal cancer and for female carriers 40-60% risk of endometrial cancer and 10-15% risk of ovarian cancer. The perceived risk among mutation carriers may, however, deviate from the risk communicated and has been demonstrated to influence adherence to control programs. We investigated the perceived cancer risk among HNPCC mutation carriers (n = 47) and correlated the findings to individual characteristics. A perceived risk of colorectal cancer above 60% was reported by 22/45 individuals, and only one out of five mutation carriers reported a perceived risk > 80%. Female mutation carriers, individuals below age 50, and individuals who received their oncogenetic counseling within 1 year prior to the study reported higher, albeit not significantly, perceived risks of colorectal cancer. Higher perceived risks were also reported by individuals who had lost a parent to HNPCC-related cancer at early age, whereas individuals with a personal history of cancer did not report a higher perceived risk. Regarding gynecological cancer, 6/18 females reported a perceived risk of 40-60% for endometrial cancer, whereas the remaining women both underestimated and overestimated their risk, and none of the women referred to the risk of ovarian cancer. We conclude that despite educational efforts and an increasing amount of data on the cancer risk in HNPCC, a minority of the mutation carriers report a perceived risk at the same level as that communicated during oncogenetic counseling.

Background: A growing number of individuals are diagnosed with hereditary cancer. Though increased levels of anxiety and depression have been demonstrated around the time of genetic counselling, most individuals handle life at increased risk well. Data have, however, been collected on individual basis, which led us to focus on family perspectives of hereditary cancer. Methods: Lynch syndrome represents a major type of hereditary colorectal and gynaecological cancer. We preformed open-ended interviews with 27 informants from 9 Lynch syndrome families. Inductive content analysis revealed three major themes: transition to a risk family, patterns of communication and influence on family relations and individual roles. Results: Family members described how learning about Lynch syndrome shifted focus from daily issues to concerns about cancer. Changes in communication related to difficulties in talking to children about heredity and informing new family members and distant relatives about an increased risk of cancer. Influence on relations was exemplified by family members taking on different roles, e. g. females often being responsible for coordinating information about heredity and providing support. Families in which members had experienced cancer at young age typically informed children soon after learning about heredity and at young age, whereas families with experience of cancer at higher age postponed information and thereby also genetic counselling. Conclusions: Three major family perspectives are described in Lynch syndrome families; becoming a risk family, patterns of communication and influence on family relations. Since these issues are central, our findings suggests that such family perspectives should be considered during genetic counselling in order to contribute to information spread, help family members cope with the increased risk, and motivate family members at risk to undergo surveillance.

Heredity represents the strongest risk factor for ovarian cancer with disease predisposing mutations identified in 15% of the tumors. With the aim to identify genetic classifiers for hereditary ovarian cancer, we profiled hereditary ovarian cancers linked to the hereditary breast and ovarian cancer (HBOC) syndrome and the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Genome-wide array comparative genomic hybridization was applied to 12 HBOC associated tumors with BRCA1 mutations and 8 HNPCC associated tumors with mismatch repair gene mutations with 24 sporadic ovarian cancers as a control group. Unsupervised cluster analysis identified two distinct subgroups related to genetic complexity. Sporadic and HBOC associated tumors had complex genetic profiles with an average 41% of the genome altered, whereas the mismatch repair defective tumors had stable genetic profiles, with an average 18% of the genome altered. Losses of 4q34, 13q12-q32 and 19p13 were overrepresented in the HBOC subset. Discriminating genes within these regions include BRCA2, FOXO1A and RB1. Gains on chromosomes 17 and 19 characterized the HNPCC tumors, but target genes herein are unknown. The results indicate that HBOC and HNPCC associated ovarian cancer develop along distinct genetic pathways and genetic profiles can thus be applied to distinguish between different types of hereditary ovarian cancer.

Background: Identification and adequate management of individuals at risk for hereditary nonpolyposis colorectal cancer (HNPCC) is crucial since surveillance programmes reduce morbidity and mortality. We investigated knowledge about key features of HNPCC in at risk individuals and physicians in surgery, gynecology and oncology. Methods: Data were collected using a questionnaire which was answered by 67 mutation carriers and 102 physicians from the southern Swedish health care region. The statements were related to colorectal cancer, heredity and surveillance and the physicians were also asked questions about cancer risks and surveillance strategies. Results: Both groups answered questions on colorectal cancer risk, surveillance and genetic testing well, whereas answers about inheritance and risks for HNPCC associated cancer were less accurate. Only half of the family members and one third of the physicians correctly estimated the risk to inherit an HNPCC predisposing mutation. Among family members, young age (<57 years), female sex and recent genetic counseling significantly correlated with better results. Physicians generally underestimated the risk of HNPCC associated cancers and three out of four suggested a later starting age for surveillance than recommended. Conclusion: The finding of similar levels of knowledge about key features of HNPCC in at risk individuals and physicians reflect the challenge physicians face in keeping up to date on hereditary cancer and may have implications for the clinical management and professional relations with HNPCC family members.

At least one of ten patients with ovarian cancer is estimated to develop their tumor because of heredity with the breast and ovarian cancer syndrome due to mutations in the BRCA1 and BRCA2 genes and hereditary nonpolyposis colorectal cancer (HNPCC) being the major genetic causes. Cancer at young age is a hallmark of heredity, and ovarian cancers associated with HNPCC have been demonstrated to develop at a particularly early age. We used the Swedish Cancer Registry to identify a population-based series of 98 invasive epithelial ovarian cancers that developed before 40 years. Mucinous and endometrioid cancers were overrepresented and were diagnosed in 27% and 16% of the tumors, respectively. Immunostaining using antibodies against MLH1, PMS2, MSH2, and MSH6 was used to assess the mismatch-repair status and revealed loss of expression of MLH1/PMS2 in two cases, loss of MSH2/MSH6 in one case, and loss of MSH6 only in three tumors. A microsatellite instability–high phenotype was verified in five of six tumors. Based on the identified mutations and family history of cancer, several of these individuals are likely to be affected by HNPCC. We conclude that although the causes of the vast majority of epithelial ovarian cancer at young age are unknown, HNPCC should be considered because of the high risk of metachronous colorectal cancer in the individual and the possibility of preventing additional cancers in the family through control programs.

Background. Multidisciplinary team (MDT) conferences have been introduced into standard cancer care, though evidence that it benefits the patient is weak. We used the national Swedish Rectal Cancer Register to evaluate predictors for case discussion at a MDT conference and its impact on treatment. Material and methods. Of the 6760 patients diagnosed with rectal cancer in Sweden between 2007 and 2010, 78% were evaluated at a MDT. Factors that influenced whether a patient was discussed at a preoperative MDT conference were evaluated in 4883 patients, and the impact of MDT evaluation on the implementation of preoperative radiotherapy was evaluated in 1043 patients with pT3c-pT4 M0 tumours, and in 1991 patients with pN + M0 tumours. Results. Hospital volume, i.e. the number of rectal cancer surgical procedures performed per year, was the major predictor for MDT evaluation. Patients treated at hospitals with less than 29 procedures per year had an odds ratio (OR) for MDT evaluation of 0.15. Age and tumour stage also influenced the chance of MDT evaluation. MDT evaluation significantly predicted the likelihood of being treated with preoperative radiotherapy in patients with pT3c-pT4 M0 tumours (OR 5.06, 95% CI 3.08 - 8.34), and pN + M0 (OR 3.55, 95% CI 2.60 -4.85), even when corrected for co-morbidity and age. Conclusion. Patients with rectal cancer treated at high-volume hospitals are more likely to be discussed at a MDT conference, and that is an independent predictor of the use of adjuvant radiotherapy. These results indirectly support the introduction into clinical practice of discussing all rectal cancer patients at MDT conferences, not least those being treated at low-volume hospitals.

Cancer patient associations report a growing number of members and increasing possibilities to influence health care, but knowledge about the members' views on the benefit of involvement is scarce. We therefore investigated how members (n = 1742) of Swedish patient associations for breast cancer and prostate cancer rate the benefit of membership for their physical and psychological well-being and social adjustment to cancer. Using a scoring scale, 2/3 of the members reported that membership had benefit for psychological well-being, whereas half of the members reported benefit for physical well-being and social adjustment. Individuals who had been actively involved in board work and/or contact person activities within the associations reported significantly more benefit for all three parameters. Gender differences were observed with men, represented by individuals affected by prostate cancer, reporting greater benefit for all three parameters, although especially evident for psychological well-being. Individuals who obtained membership within two years of diagnosis reported greater benefit for psychological well-being and social adjustment compared to those who became members later. In conclusion, members in patient associations for cancer report benefit particularly for their psychological well-being and actively involved members and men affected by prostate cancer perceive the greatest benefit from membership.

Background: Patients needs and experiences attract increasing attention within health care. In order to generate knowledge about the voices that emerge from collaborative experiences between members of patient associations for cancer patients ( PACP) and health care professionals (HCPs), we studied a permanent network aimed at improving cancer care through increased attention to the cancer patients' view and experiences. Methods: Open-ended interviews were carried out with 16 individuals; 6 PACP members and 10 HCPs, and after transcription the texts were analysed by inductive content analysis. Results: Four voices, which represent various experiences from networking, were identified; the hesitant voice, the enlightened voice, the liberated voice, and the representative voice. The hesitant voice reflects uncertainty experienced when the participants were exposed to different views and opinions within the network. The enlightened voice reflects new points of view and gain of knowledge. The liberated voice signifies trust, balance, and confidence related to individual experiences and responsibilities being viewed in a broader perspective. The representative voice is derived from the transformation of experiences and responsibilities through insight, understanding, and new perspectives. Conclusion: Networking between representatives for PACPs and HCPs may help the participants manage uncertainty, strengthen the patient's perspective and provide new views on common issues. The different voices identified in this study demonstrate that both PACP members and HCPs distanced themselves from their individual experiences in order to be perceived as unselfish and knowledgeable within the network. Although the climate was characterized by trustfulness, the members' unique positions need to be defined in order to obtain an optimal balance between the groups and prevent members' patient experiences of losing their character by learning to much from the HCPs. Increased understanding of the hesitant, the enlightened, the liberated, and the representative voices, and awareness of experiential versus professional knowledge of cancer may facilitate and probably improve future networking efforts.